Sinomenium acutum is a common Chinese medicinal plant. The name “Sinomenium acutum” first appeared in the Song Dynasty. It is recorded in detail in “Atalas of Matria Medica” and “Catalogs of Materia Medica.” It has anti-rheumatioid and analgesic properties. It has been used in the treatment of rheumatoid arthritis (RA), pain and numbness in extremities, injuries and inflammation. It is mostly distributed in Shanxi, Henan, Hubei, Jiangsu, Anhui, Zhejiang, Jiangxi, and Fujian provinces in China. The stem and roots of Sinomenium acutum contain sinomenine, sinoacutine, disinomenine, ethylsinomenine, isosinomenine, sinactine, acutumine, acutumidine, tuduranine, and magnoflorine. It also contains small amounts of stepherine, mechelalbine, dl-syngaresinol, β-sitosterol, and stigmasterol.

Sinomenine, 1, is an isoquinoline alkaloid isolated from Sinomenium acutum. Its chemical name is (9a,13a,14a)-7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methyl-morphonan-6-one. Its molecular formula is C19H23NO4, and its molecular weight is 329.38, and its optical rotation is [α]20D=−71°, (c=2.1, ethanol). The structure of sinomenine is similar to that of morphinoids and is composed of a hydrophenanthrene nucleus with a ethylamine bridge, containing four rings and three optical active centers. Its structure and compound number are as shown in the above figure.
Sinomenine has anti-inflamatory, immune suppression, analgesic, anti-hypertension, anti-irrythmia pharmacological activities. It is used in the clinics to treat rheumatoid arthritis and irrythmia. Treatment of rheumatoid arthritis is the best defined clinical use of sinomenine. Currently, the dosages used in the clicnic include Zhenqingfeng pain relief tablets, sinomenine slow release tablets, sinomenine HCl injection, and sinmenine tablets. The main route of administration is oral administration, intramuscular injection, injection at the acupuncture points, and iontophoresis. Rheumatoid arthritis is an autoimmune disease characterized with inflammation at synovial joint. Repeated occurrence of synovial joint inflammation can lead to damages of cartilage and bone in the joint, impairment of joint function, and even disability. Rheumatoid arthritis still has no effective treatment; most treatments still remain at controlling the inflammation and the after-effects. At the moment, medications used in the treatment of rheumatoid arthritis are mainly non-steroidal anti-inflamatory drugs (NSAID), as represented by Aspirin, corticoid steroid drugs, disease modulator such as gold containing preparations (Auranofin), penicillamine, chloroquine, levamisole, immune suppresors (such as Methotrexate (MTX)), Chinese medicine Tripterygium Wilfordii, yunnan begonia, and sinomenine Relative to other medications, sinomenine has a unique structure. As compared with the well studied NSAID, research of sinomenine is very preliminary. Therefore, it is uniquely valuable to study the properties of sinomenine.
Sinomenine when used as a single agent in the clinic has the following drawbacks: the in vivo half life of sinomenine is relatively short and large doses are needed. In addition, it is typically taken orally for a long time. Sinomenine has a strong histaminic effect. In clinical use, it often causes skin rash, and it is often accompanied with gastric intestinal irritation side effects. Furthermore, sinomenine is unstable to light and heat; it is susceptible to degradation.
Therefore, there have been a wide range of research and reports on the dosage of sinomenine with respect to how to enhance its therapeutic effects, lower its toxic side effects, and change its irritative properties and instability. By using a proper dosage form, such as new dosage forms of slow release, controlled release, gels, and sprays, the clinical therapeutic effects of sinomenine to some extent are indeed improved and the adverse reaction is reduced, resulting in certain outcome. However, it is difficult to completely alleviate the above noted drawbacks of sinomenine simply by changing the dosage forms. To achieve that goal, it is necessary to modify the structure of sinomenine, to embark on medicinal chemistry research and improvement, in order to achieve new sinomenine derivative with high potencies and low toxicities.
To date, many research institutions in China have initiated research projects on sinomenine. This provides a unique Chinese perspetive on sinomenine. Xianrong Ye (Pharmaceutical Report, 2004, 39(3), 180-183) reported structure modifications of sinomenine C. The research group of Guowei Qin at Shanghai Institute of Materia Medica has used sinomenne as a lead compound to develop memory enhancing drugs (WO 2004/0483401 A1). The research group of Yi Pan at Nanjing University (CN 1785976A, CN 1786977A, CN 1821244A), the research group of Jianxin Lee at Nanjing University (CN 101265266A, CN 101148437A), Hunan Zhenqing Pharmaceutical Group, Ltd. Co. (CN 1876634A), Xichuan University (CN 1800164A, CN 1948291A), our research group (CN 1687065A, CN 1687070A), and WO 2007/07070 all have studied structure modifications of sinomenine chemicals with respect to their anti-inflamatory and anti-immune activities.
The chemical structure of sinomenine contains a phenol group, which is easily oxidized in the presence of an oxidant. Therefore, we studied the reactivity of sinomenine under oxidative conditions and obtained a series of derivatives with novel structures. Furthermore, using TNF-α inhibition experiments, we have assessed the activities of these new derivatives.
The cellular origins of TNF-α covers a wide range, including various immune cells, endothelial cells, fibroblasts, epithelial cells, keratinocytes, smooth muscle cells, asterocytes, osteoblasts, etc. The macrophages in heart tissue are good sources for the inflamatory cytokine, TNF-α. Human TNF-α gene encodes a propeptide; its signal peptide sequence anchors the propeptide to the cell membrane, resulting in an active transmembrane interferon. After cleavage of the signal peptide by an enzyme, it produces a secretory TNF-α, with a molecular weight of 17 kD. NF-κB and p38-MAPK signal pathways participate in the expression of TNF-α. TNF-α has a wide range of biological activities, such as involvement in inflamation reaction and immune response, antitumor, involvement in the endotoxic shock pathological processes, leading to cachexia. TNF-α has dual functions: on the one hand, it plays an important role in organism immune regulation, physiological function, and counter infections. On the other hand, if TNF-α is continuously produced or over-produced, it will lead to fever, shock, and cachexia. At the same time, TNF-α can further induce IL-6, IL-8, and IL-10 cytokine productions. These inflamatory cytokines are involved in accute response and fever responses, which result in the release of chemotatic peptides, and activation of endothelial cells, which results in the increased permeability of the blood vessels.
The functions of TNF-α in rheumatoid arthritis: TNF-α is a pro-inflamatory cytokine that plays a central role in the mechanism underlying the development of rheumatoid arthritis; it is involved in the initiation and development of rheumatoid arthritis. TNF-α is mainly produced by macrophages. It can induced the production of other inflammation factors such as interleukin-1 (IL-1) and interleukin-6 (IL-6). It can activate adhesion molecules, enhance the production of metallo proteases, inhibit the synthesis of cartilage proteoglycans, leading to bone and cartilage damages. Currently, clinical treatments of autoimmune rheumatoid arthritis mainly use anti-TNF-α antibodies and soluble TNF-α receptor fusion proteins. Good treatment results have been obtained. Using in vitro assays to assess the inhibition of TNF-α by chemical compounds, one can effectively evaluate the anti-inflamatory and immune suppression activities of the compounds.